Periodontal diseases are a major dental affliction to mankind. Periodontitis, inflammation and progressive loss of ligament and alveolar (socket) bone support to tooth, is caused by bacteria which colonize tooth surfaces and occupy the gingival crevice area. Extraction of impacted third molars in close proximity to erupted second molars can also leave damage or loss of support to the second molars.
Regeneration of lost periodontal tissues is a goal of periodontal therapy but is usually not achieved to a maximum or desired level. This is due to the complexities and difficulties associated with periodontal wound healing: Infected, degraded or effete tissue elements must be digested and eliminated and the healing site must be kept free of pathogens. Populations of progenitor cells with the capacity to undergo extensive cell division must be adjacent to the wound site. The dividing cells must respond to soluble and matrix factors by appropriate numbers of mitoses and differentiation steps to become specialized, synthetic cells. The progenitor and specialized cells must migrate to the appropriate site for matrix synthesis. At the wound site, self-renewing cell populations must be established to repopulate the tissue for longterm maintenance. The nascent matrix and attachment components must be stably integrated and undergo remodeling to restore tissue architecture and function. Finally, the repopulating cells must be able to synthesize appropriate growth, differentiating and signaling factors to restore dynamic tissue homeostasis. See C. A. G. McCulloch, Periodontal Regeneration, pp. 16-25, Periodontology 2000, Volume 1 Munksgaard, Copenhagen, 1993. The progenitor cells must differentiate into cementoblasts (to form new peripheral hard root surface covering or cementum), fibroblasts (to form new periodontal ligament) and osteoblasts (to form new supporting alveolar bone). Moreover, the periodontal ligament must integrate appropriately with surface covering or cementum), fibroblasts (to form new periodontal ligament) and osteoblasts (to form new supporting alveolar bone). Moreover, the periodontal ligament must integrate appropriately with both the new cementum and bone to form a complete and truly functional periodontal attachment apparatus. Further, this regeneration of periodontal tissues should yield maximum regeneration of lost periodontal tissues along the avascular root surface. These criteria are very difficult to achieve and are rarely met clinically. Therefore, efficacy and predictability are major problems in periodontal regeneration.
A large array of peptide growth and migration factors have been identified. A group of naturally occurring molecules known as polypeptide growth factors in conjunction with certain matrix proteins are key regulators of the biological events of migration, attachment and proliferation of cells. Of these, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), transforming growth factor (TGF) and epidermal growth factor (EGF) appear to have an important role in periodontal wound healing. See R. G. Caffesse and C. R. Quinones, Periodontal Regeneration, pp. 69-79, Periodontology 2000, Volume 1 Munksgaard, Copenhagen, 1993.
During the initial phases of periodontal wound healing, a fibrin clot is formed at the site of the periodontal procedure (e.g., periodontal flap surgery). This constitutes the first step toward formation of the extracellular matrix. Various cells involved with the healing process actively contribute to the formation and organization of this matrix. Besides serving as a substrate, it contains a number of secreted biologically active factors acting as chemoattractants and biomodulators that trigger a variety of responses from the cellular components of the healing site. See S. Amar and K. M. Chung, Clinical Implications Cellular Biologic Advances in Periodontal Regeneration, p.p. 128-140, Current Opinion in Periodontology, Current Science, Philadelphia, 1994. Outcomes, however, usually result in incomplete periodontal regeneration due to the aforementioned difficulties in periodontal regeneration coronally (toward the crown of the tooth) along the root surface and competitive epithelial downgrowth along the internal aspect of the soft tissue wound (e.g., the repositioned periodontal surgery flap).
Periodontal guided tissue regeneration membranes have been developed and used, upon surgical placement, to separate the tooth root, periodontal ligament and bone from the gingival soft tissues (periodontal or surgical flap) to blockade epithelial downgrowth along the soft tissue wound. This allows for independent regeneration of lost periodontal tissues along the root surfaces. Again, outcomes are equivocal in both efficacy and predictability as this technology does not address optimization of the regenerative system. It acts solely as a mechanical blockade to segregate healing tissue compartments.
Applicant's U.S. Pat. Nos. 5,059,123 and 5,197,882 deal with the sustained, controlled release of chemotherapeutic agents from microshapes incorporated into periodontal barriers to effect a more favorable periodontal regeneration by the use of these agents to enhance cellular healing events and/or diminish negative healing factors (e.g., infection). Applicant's previous method does not address a specific application to the root surface to optimize periodontal regeneration events along this surface.
Applicant's U.S. Pat. No. 4,685,883 deals with local delivery of chemotherapeutic agents to the periodontal defect for sustained, controlled release by either incorporation into microshapes introduced into the defect or by adhesively positioning a biodegradable matrix, including a chemotherapeutic agent thereon, subgingivally on the root surface within the periodontal pocket. Applicant's previous method here does not specifically address the important cofactor of enhancing cell migration along the root surface with maximum coronal periodontal tissue regeneration.
Application of agents against the root surface, by surgical placement, to augment healing has been studied. IGF-1 and PDGF, in combination with methylcellulose gel, were used by syringe application during periodontal surgery in beagle dogs to enhance periodontal regeneration. See S. E. Lynch, R. C. Williams and A. M. Polson, et al, A Combination of Platelet-Derived and Insulin-Like Growth Factors Enhances Periodontal Regeneration. J Clin Periodontal 16:545-548, 1989. The coordinated regrowth of the periodontium seen in this study may be due to the ability of PDGF and/or IGF-1 to attract all the cell types necessary for the formation of all of the periodontal tissues with stimulation of proliferation as these cells migrate into the wound site. Although the periodontal regeneration was significant relative to controls, it was limited. The duration of the PDGF/IGF-1 in the region was relatively short-lived and may have contributed to the lack of a more complete healing along the root surface. Further, no specific mechanism of enhancing cell migration along the root surface was addressed.
Study of the cellular recognition of several proteins which interact with cell surfaces led to the observation that three amino acids--an arginine-glycine-aspartic acid (RGD) tripeptide--are crucial for their interaction with cell surface receptors. See E. Ruoslahti and M. D. Pierschbacher, Arg-Gly-Asp: A Versatile Cell Recognition Signal, Cell 44:517-518 (1986). Many adhesive proteins present in extracellular matrices and in blood contain RGD as their cell recognition site. These include fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen and von Willebrand factor. The RGD sequences of each of the adhesive proteins are recognized by at least one member of a family of structurally related receptors, cell integrins, which can bind to the RGD sequence of adhesion proteins. Some of these receptors bind to the RGD sequence of a single adhesion protein only, whereas others recognize groups of them. Together, the adhesion proteins and their receptors constitute a versatile recognition system providing cells with anchorage, traction for migration, and signals for polarity, position, differentiation and possibly growth. Sao E. Ruoslahti and M. D. Pierschbacher, New Perspectives in Cell Adhesion: RGD and Integrins, Science 238: 491-497 (1987).
The present invention solves problems in the regeneration of lost periodontal tissues by optimizing the availability of tissue regenerative agents along the root surface in the site of desired periodontal regeneration and by enhancing cellular migration, differentiation, proliferation and maturation of the regenerative periodontal tissues along the root surface for maximal regeneration.